The companion metabolic diseases, diabetes and obesity, are rapidly becoming the major health concern of western societies. The failure to accurately sense and respond to cellular metabolic status is a key factor in the pathogenesis of both diseases. We have shown that the protein kinase PAS kinase (PASK) is a sensor of cellular metabolic state that might play a role in obesity and diabetes. One of the most dramatic effects of PASK loss is protection from the highly deleterious ectopic lipid accumulation in liver typically observed in wild-type mice. The goal of this grant is to determine the role of PASK in regulating hepatic lipid metabolism in response to cellular metabolic state. This will be accomplished through the following specific aims: I. We will determine how PASK is regulated by both cellular and hormonal cues related to metabolic state. II. We will determine the mechanisms whereby PASK regulates hepatic lipid metabolism, focusing on regulation of SREBP-1, initially using a cultured cell model. III. We will determine whether PASK acts directly in the adult liver to affect transcription, lipid metabolism and glucose homeostasis using four new models of altered PASK expression. PUBLIC HEALTH RELEVANCE: Obesity and diabetes are rapidly becoming the major health concern of western societies. A key aspect of both of these diseases is the inappropriate accumulation of fat or lipid in tissues such as the liver. We have shown that elimination of one specific gene, PAS kinase, prevents this liver lipid accumulation, at least under some situations. The purpose of this grant is to determine the mechanism(s) whereby PAS kinase regulates liver lipid accumulation and to extend these observations to directly assess the feasibility of PAS kinase as a therapeutic target in metabolic disease.